Lecture 14 Notes.pdf

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Lecture 14: The Control of Breathing (continued)
1. Summary of the Control of Breathing
Breathing is produced in the respiratory control centres of the medulla oblongata and the pons,
in the brainstem. A “basic rhythm of breathing” is produced and then modified by a host of
inputs from various (central) chemoreceptors in the brain, peripheral chemoreceptors in the
arteries, stretch receptors in the lungs receptors in the muscles and joints as well as irritant
receptors in the lungs. We are not particularly concerned with the receptors in the muscles and
joints, but in short, while we all know that breathing increases during exercise, there is no known
respiratory control system that can account for the increase. It is thought that this increase in
breathing may actually be caused by mechanoreceptors or proprioceptors, rather than receptors
that are specifically respiratory-related in nature.
2. The Pontine Respiratory Group (PRG)
The Pontine Respiratory Group (PRG) is located in the pons. It consists of two main nuclei,
the Kölliker Fuse and the Nucleus Parabranchialis. It plays an important role in the
termination of inspiration and the correct switching from inspiration to expiration. Later, we'll
see that this is actually a good example of redundancy in respiratory control systems, because
the stretch receptors in the lungs perform the same function. For important control systems, such
as respiration or heart function, redundancy in control systems help to increase the chances of
survival if one of the primary (or the primary) control systems should fail. The PRG is also
called the apneustic centre because if the connection between the midbrain and the pons is
severed, then apneustic breathing (prolonged inhalation) results.
3. The Dorsal Respiratory Group (DRG)
The Dorsal Respiratory Group (DRG), which is approximately the same (in most animals,
including humans) with the nucleus tractus solitarius in the medulla oblongata, is an important
relay center for both respiratory and cardiovascular control system input. It is the site of the first
synapse of carotid sinus baroreceptors and aortic arch baroreceptors, as well as carotid body O
2
chemoreceptors. Pulmonary stretch receptors also report to the NTS. The DRG is an important
relay centre, taking in this respiratory-related information and sending signals to the ventral
respiratory group as well as to some respiratory motor neurons.
4. The Ventral Respiratory Group (VRG)
The Ventral Respiratory Group (VRG) consists of three main nuclei: the Bötzinger Complex,
the Nucleus Ambiguous and the Nucleus Retroambiguous. It is essentially an integrative
center, taking neural input from the DRG and the rhythm generator and then “modifies” this
information to produce the motor output that ultimately drives the respiratory muscles. It is made
up of inspiratory neurons some of which project to the respiratory motor neurons, some project
within the VRG, and some fire only during active expiration (for example, during exercise). 2
5. The Pre-Bötzinger Complex
The site of respiratory rhythm generation (the basic kernel of breathing) is the respiratory rhythm
generator which appears to be located in two regions of the brain with the primary function being
in the Pre-Bötzinger Complex. It is located in the ventral region of the brain, very close to the
Bötzinger Complex of the VRG. The rhythm generator acts as the “pacemaker” for breathing.
Neural activity generated in the Pre-Bötzinger Complex goes to the VRG for modification before
being transmitted along the respiratory motor neurons to drive the respiratory muscles.
The importance of the Pre-Bötzinger Complex can be seen when it is disabled - breathing
becomes ataxic, and very irregular - and if the complex is completely destroyed, breathing ceases
altogether. Generally, this would mean death - however, if an animal with a destroyed Pre-
Bötzinger Complex is put on artificial ventilation for an hour or so (immediately following
destruction of the Pre-Bot), breathing will eventually resume spontaneously. This indicates that
there is a redundant rhythm generator located in the brain (though generally, if the Pre-Bötzinger
Complex is destroyed, the redundancy cannot take over quick enough to prevent death). It is now
known that the Pre-Bötzinger Complex works together with the Parafacial Nucleus (which is
located right beside it) to act as a pacemaker, and given enough time the Parafacial Nucleus can
take over as pacemaker if need be.
6. Models of Respiratory Rhythm Generation and Respiratory-Related Neurons
Respiratory control is an extremely complicated and complex process, with many different
nerves acting in different ways and firing at different times with respect to inspiration and
expiration. The phrenic nerve, for example, ramps up in activity during inspiration, before
reducing its activity during expiration and ending in a period of no activity before the next
breath. Early Inspiration neurons are active during and slightly before inspiration, whilst ramp
inspiration neurons are only active during inspiration. Late inspiration neurons are only active in
a short burst towards the end of inspiration, whilst post-inspiration neurons are only active after
inspiration. Type two early inspiration neurons only fire a while before a breath is taken, as do
pre-inspiration neurons. All in all, there are perhaps twenty to twenty-five different types of such
neurons, depending on how one classifies them.
7. Arterial Oxygen Chemoreceptors: The Carotid Body
The primary site of oxygen sensing in the arterial blood are the arterial oxygen chemoreceptors
located within the carotid body. The carotid body is found at the bifurcation of the carotid artery,
and on a per-weight basis the carotid body receives more blood flow than any other part of the
body. There are two cell types in the carotid body, of which Type I (glomus) cells are the O 2
sensors. The discovery of the carotid artery, by Corneille Heymans, occurred almost
accidentally, when he injected cyanide into the carotid artery of an anesthetized dog. The cyanide
stimulated the oxygen sensors of the carotid body, leading to a huge increase in breathing. For
this discovery, Corneille Heymans received the 1938 Nobel Prize in medicine.
The carotid body is innervated by the carotid sinus nerve, which joins the 9th cranial nerve 3
before reporting to the brainstem. The carotid afferents report to the nucleus tractus solitarius in
the medulla oblongata. The glomus cells, which are the oxygen-sensing cells in the carotid body,
release a number of neurotransmitters, mainly acetylcholine and dopamine. Acetylcholine acts
post-synaptically on the carotid sinus nerve whilst dopamine acts as a feedback inhibitor on the
glomus cells to prevent further acetylcholine release.
8. The Mitochondrial Model of Oxygen Chemoreception
It is still not entirely known how the carotid body senses oxygen. However there are a number of
hypotheses and models. One of the original models is the mitochondrial model of oxygen
sensing. This proposed mechanism occurs in the electron transport chain within the mitochondria
of glomus cells. Electrons travel along the chain and ultimately the electrons (in the form of
hydrogen ions) are passed to O to2form water. This happens in all cells, but the theory states that
in the O 2chemoreceptors cells, the cytochrome C complex that completes the reduction of O to 2
H 2 is extra-sensitive to low levels of O .2Under hy+oxic conditions, O leve2s are diminished,
and so the conversion of O to2H O i2 slowed. H ions build up along the inner membrane of the
mitochondria (in the mitochondrial matrix) causing the inner mitochondrial